Curcumin in Combination with Other Adjunct Therapies for Brain Tumor Treatment: Existing Knowledge and Blueprint for Future Research

Malignant brain tumors proliferate aggressively and have a debilitating outcome. Surgery followed by chemo-radiotherapy has been the standard procedure of care since 2005 but issues of therapeutic toxicity and relapse still remain unaddressed. Repurposing of drugs to develop novel combinations that can augment existing treatment regimens for brain tumors is the need of the hour. Herein, we discuss studies documenting the use of curcumin as an adjuvant to conventional and alternative therapies for brain tumors. Comprehensive analysis of data suggests that curcumin together with available therapies can generate a synergistic action achieved through multiple molecular targeting, which results in simultaneous inhibition of tumor growth, and reduced treatment-induced toxicity as well as resistance. The review also highlights approaches to increase bioavailability and bioaccumulation of drugs when co-delivered with curcumin using nano-cargos. Despite substantial preclinical work on radio-chemo sensitizing effects of curcumin, to date, there is only a single clinical report on brain tumors. Based on available lab evidence, it is proposed that antibody-conjugated nano-curcumin in combination with sub-toxic doses of conventional or repurposed therapeutics should be designed and tested in clinical studies. This will increase tumor targeting, the bioavailability of the drug combination, reduce therapy resistance, and tumor recurrence through modulation of aberrant signaling cascades; thus improving clinical outcomes in brain malignancies.

glioma (2). Looking at the treatment outcomes in the last 15 years, in terms of survival and quality of life of patients, this therapy regimen needs improvement. The major hitches in brain tumor treatment are: lack of gross total surgical resection due to the tumor location, presence of the bloodbrain barrier (BBB) that doesn't allow the entry of majority of the chemotherapeutic agents into the brain, infiltrative nature of the tumor, toxicity, and resistance induced by the prolonged administration of chemo-radiotherapy. This clinical scenario necessitates the repurposing of established, nontoxic therapeutic agents as an adjunct to overcome treatment-induced resistance, reduce its side effects, and prevent a recurrence.
The present century has witnessed a resurrection of interest in complementary medicine for the development of alternative agents in the treatment of neoplasms. Currently, few of the primary and adjuvant therapies being explored for brain cancers like resveratrol, curcummin (CUR), berberine, quercetin, genistein, etc (3)(4)(5)(6)(7) are derived from natural sources. These nutraceuticals are functional foods with anti-cancerous propensities due to their anti-oxidant and anti-inflammatory character. Among these CUR has stood out as a strong contender as for centuries, turmeric has been used in the Indian Ayurvedic system due to its potent anti-inflammatory, antioxidant and antiinfective properties. It is the principal curcuminoid (77%) derived from the rhizome of the perennial herb Curcuma longa (8). The rhizome is commonly known as turmeric, which is an integral spice of almost all Indian cuisines. For centuries, turmeric has been used in the Indian Ayurvedic system due to its potent anti-inflammatory, antioxidant and anti-infective properties. However, its anticancerous properties were deciphered in 1985 when Kuttan and colleagues, published their first positive preclinical report on its active constituent 'CUR' (9). This was further validated by their clinical study (10). Since then CUR has been reported for its anti-cancerous effects in various cancers including brain tumors (11,12). CUR is now known to be toxic to the cancer cells, with minimal or no toxicity towards normal cells (13,14). Its anti-cancerous properties are attributed to its pleiotropic biological effects viz. inhibition of proliferation, survival, invasion, angiogenesis, metastasis, epithelial to mesenchymal transition (EMT), and cancer stem cells (CSCs) differentiation. The dietary polyphenol has shown an exceptional safety profile in clinical trials; being nontoxic even at a dose of 8 g/day (15). All these factors put together endorse its use as an adjunct to conventional therapies. The US Food and Drug Administration (FDA), has approved the yellow spice as GRAS (generally recognized as safe).
Treatment with single agents, whether synthetic or natural, has limitations since brain tumors present intra-tumor genomic and cellular heterogeneity (16). Therefore, the focus of current  (18,19). The approach to overcoming these barriers is to sensitize tumor cells by using CUR to potentiate the activity of onco-therapeutics via modulation of one or more mechanisms of resistance.

Curcumin inhibits inflammation
Inflammation is a natural immune reaction to  (26,27).   (29,31). CUR has also been shown to trigger DNA damage and inhibit the expression of MGMT (32).

Curcumin inhibits CSC's and EMT phenomenon
Resistance to standard treatment modalities is also attributed to the existence of two other factors  Similarly, CUR was reported to work as an

CUR as a sensitizer for other repurposed chemotherapeutic agents
Apart from the above-mentioned drugs, some other therapeutics have been tested in conjunction with CUR in vitro to assess their anti-proliferative and apoptosis-inducing efficacy in brain malignancies (Table 1)

CUR as a sensitizer for radiotherapy
In addition to the synergistic effect of CUR with chemotherapy, the polyphenol has also exhibited plausible utility in sensitizing glioma cells to radiation-induced cell death (Table 1). When radio-resistant human glioma cells were pre-treated with CUR followed by irradiation, it resulted in a significantly enhanced cell death (43). Increasing the bioavailability of CUR using nanoparticles The most intimidating task for a chemotherapeutic used in the treatment of brain malignancies is crossing the BBB to facilitate effective drug dose accumulation in the brain.
Despite its promising pharmaceutical characteristics CUR has some major drawbacks limiting its application as an anti-cancer therapeutic agent.
CUR is known to possess the ability to cross the BBB, evident from an in vitro experiment on the brain-capillary model (55). Its poor physicochemical properties namely low water solubility and enzymatic conversion to glucuronide derivatives, and rapid clearance from circulation result in poor bioavailability, thereby limiting its    (59).

Nanoparticle mediated delivery of CUR and other drugs
The use of drugs loaded onto nanoparticles is enticing the attention of the neuro-oncology fraternity, due to its exceptional potential for targeted brain delivery ( Table 3). The combination of CUR and rapamycin-loaded micelles exhibited

Nanoparticle mediated delivery of CUR and other natural products
Apart from the nanoformulation-based studies above, CUR has also been delivered with some natural plant compounds (Table 3). Liposome

Curcumin tagged to antibodies
It is postulated that antibody-mediated homing of cancer cells would result in higher levels of a drug at the tumor site, thus intensifying CUR's effectiveness (Table 4)   activation, which resulted in successful apoptosis, and increased tumor cytotoxicity (74).

CUR delivered with other drugs under magnetic influence
Various research groups in the past decade have experimented with different brain targeting strategies for co-delivery of CUR and standard chemo-drug using nanoparticles under the magnetic influence with or without ligands; to achieve better treatment endpoints (Table 4) glioma-bearing mice. The adjunct therapy led to a ten times higher cellular uptake in the GB cells compared to non-targeted nanoparticles. It also improved survival in the mice model (77).

Clinical report
There are various clinical trials of CUR in different cancers (78). Despite substantial preclinical data available on brain tumors, clinical reports/trials documenting CUR as a therapeutic singularly or as an adjuvant are scarce (56,79). As of date, only a single clinical case report has documented the use of CUR as an adjuvant in brain malignancy. This case presentation is of a 60-year-  should also be tried and tested in combination with CUR to increase the horizon of re-tracking de-regulate pathways in brain tumors to get improved treatment outcomes.

Limitations of previous work and future prospects
Pharmacokinetic deficiency in terms of gastrointestinal absorption and bioavailability is its most critical limitation and is a major obstacle in its use as a licensed drug (85). To address this issue further animal study should be rigorously designed for targeted delivery of CUR to the tumor site.
Another point to ponder is why post innumerable preclinical studies, regulatory approvals for the use of some very promising nano-formulations have not been taken and tested in human subjects as there is only one case study to date in brain malignancy.
Caution needs to be exercised while addressing bioavailability as the structural modification of CUR during nanoparticle synthesis may lessen its efficacy. Also, the toxic solvents used in its preparation may increase its bioavailability but limit its clinical usage and are not very costeffective (86). In light of the present critical review of literature, the strategy that has stood out as the most promising combination to be taken up for preclinical studies is a one-pot formulation, that is, antibody coupled with nano-CUR along with radiation and/or sub-toxic doses of chemo-drugs.
This approach can help accumulate a therapeutic dosage in the brain, and also prevent rapid systemic

Acknowlegement
Authors are thankful to all those who provided full text of their respective articles not available in public domain.
Authors have no conflict of interest, financial or any other to disclose.